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A Review on Novel Drug Targets and Future Directions for COVID-19 Treatment.

ABSTRACT: Severe acute respiratory syndrome coronavirus-2 causes coronavirus disease-19 (COVID-19) that spreads quickly in the world. Considering the impact of this pandemic, researchers have been racing to understand the peculiar nature of the virus and the pathogenesis of the disease to uncover possible drug targets, effective therapeutic agents, and vaccines. Accordingly, numerous drug targets are identified by scientists. Among them, structural glycoproteins, virulence factors, host-specific receptors and enzymes, non-structure proteins, the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, and pro-inflammatory cytokines are discussed herein. This review summarizes the promising drug targets for COVID-19, and highlights antiviral strategies which depend on molecular interactions between viral small molecules and host biologic machinery for repurposing the available clinical drugs. In addition, it gives a strong rational basis for the ongoing discovery of new drugs and vaccines.

SUBMITTER: Wondmkun YT

PROVIDER: S-EPMC7457863 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Review on Novel Drug Targets and Future Directions for COVID-19 Treatment.

Wondmkun Yohannes Tsegyie YT Mohammed Ousman Ahmed OA

Biologics : targets & therapy 20200825

Severe acute respiratory syndrome coronavirus-2 causes coronavirus disease-19 (COVID-19) that spreads quickly in the world. Considering the impact of this pandemic, researchers have been racing to understand the peculiar nature of the virus and the pathogenesis of the disease to uncover possible drug targets, effective therapeutic agents, and vaccines. Accordingly, numerous drug targets are identified by scientists. Among them, structural glycoproteins, virulence factors, host-specific receptors ...[more]

PMID: 32921981

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Project description:The major human liver drug metabolising cytochrome P450 (CYP) enzymes are downregulated during inflammation and infectious disease state, especially during coronavirus disease 2019 (COVID-19) infection. The influx of proinflammatory cytokines, known as a 'cytokine storm', during severe COVID-19 leads to the downregulation of CYPs and triggers new cytokine release, which further dampens CYP expression. Impaired drug metabolism, along with the inevitable co-administration of drugs or 'combination therapy' in patients with COVID-19 with various comorbidities, could cause drug-drug interactions, thus worsening the disease condition. Genetic variability or polymorphism in CYP2C9 across different ethnicities could contribute to COVID-19 susceptibility. A number of drugs used in patients with COVID-19 are inducers or inhibitors of, or are metabolised by, CYP2C9, and co-administration might cause pharmacokinetic and pharmacodynamic interactions. It is also worth mentioning that some of the COVID-19 drug interactions are due to altered activity of other CYPs including CYP3A4. Isoniazid/rifampin for COVID-19 and tuberculosis co-infection; lopinavir/ritonavir and cobicistat/remdesivir combination therapy; or multi-drug therapy including ivermectin, azithromycin, montelukast and acetylsalicylic acid, known as TNR4 therapy, all improved recovery in patients with COVID-19. However, a combination of CYP2C9 inducers, inhibitors or both, and plausibly different CYP isoforms could lead to treatment failure, hepatotoxicity or serious side effects including thromboembolism or bleeding, as observed in the combined use of azithromycin/warfarin. Further, herbs that are CYP2C9 inducers and inhibitors, showed anti-COVID-19 properties, and in silico predictions postulated that phytochemical compounds could inhibit SARS-CoV-2 virus particles. COVID-19 vaccines elicit immune responses that activate cytokine release, which in turn suppresses CYP expression that could be the source of compromised CYP2C9 drug metabolism and the subsequent drug-drug interaction. Future studies are recommended to determine CYP regulation in COVID-19, while recognising the involvement of CYP2C9 and possibly utilising CYP2C9 as a target gene to tackle the ever-mutating SARS-CoV-2.

Project description:BackgroundSince the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in discovering potential therapeutic agents for this disease. In this regard, we conducted a systematic review through an overview of drug development (in silico, in vitro, and in vivo) for treating COVID-19.MethodsA systematic search was carried out in major databases including PubMed, Web of Science, Scopus, EMBASE, and Google Scholar from December 2019 to March 2021. A combination of the following terms was used: coronavirus, COVID-19, SARS-CoV-2, drug design, drug development, In silico, In vitro, and In vivo. A narrative synthesis was performed as a qualitative method for the data synthesis of each outcome measure.ResultsA total of 2168 articles were identified through searching databases. Finally, 315 studies (266 in silico, 34 in vitro, and 15 in vivo) were included. In studies with in silico approach, 98 article study repurposed drug and 91 studies evaluated herbal medicine on COVID-19. Among 260 drugs repurposed by the computational method, the best results were observed with saquinavir (n = 9), ritonavir (n = 8), and lopinavir (n = 6). Main protease (n = 154) following spike glycoprotein (n = 62) and other nonstructural protein of virus (n = 45) was among the most studied targets. Doxycycline, chlorpromazine, azithromycin, heparin, bepridil, and glycyrrhizic acid showed both in silico and in vitro inhibitory effects against SARS-CoV-2.ConclusionThe preclinical studies of novel drug design for COVID-19 focused on main protease and spike glycoprotein as targets for antiviral development. From evaluated structures, saquinavir, ritonavir, eucalyptus, Tinospora cordifolia, aloe, green tea, curcumin, pyrazole, and triazole derivatives in in silico studies and doxycycline, chlorpromazine, and heparin from in vitro and human monoclonal antibodies from in vivo studies showed promised results regarding efficacy. It seems that due to the nature of COVID-19 disease, finding some drugs with multitarget antiviral actions and anti-inflammatory potential is valuable and some herbal medicines have this potential.

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A Review on Novel Drug Targets and Future Directions for COVID-19 Treatment.

Publications

A Review on Novel Drug Targets and Future Directions for COVID-19 Treatment.

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